The present invention refers to a process for the preparation of (1H)-benzo[c]quinolizin-3-ones derivatives of general formula (I) which involves only three steps and the use, as starting products, of commercially available, or easily preparable, compounds. The compounds of formula (I) are useful as inhibitors of 5xcex1-reductases.
The present invention refers to a process for the preparation of (1H)-benzo[c]quinolizin-3-ones derivatives of general formula (I)
wherein: 
R1, R2, R3, R4, R5, same or different, are chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cycloalkyl, aryl, heterocycle, halogen, CN, azide, NRRxe2x80x2, C1-8alkylamino, arylamino, C1-8alkyloxy, aryloxy, COOR, CONRRxe2x80x2 wherein R and Rxe2x80x2, same or different, are chosen in the group consisting of: H, C1-8alkyl, cycloalkyl, aryl, heterocycle, arylC1-8alkyl;
Q is chosen in the group consisting of: simple bond, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cycloalkyl, CO, CONR, NR, wherein R is as above defined;
W is chosen in the group consisting of: H, C1-8alkyl, C2-8alkenyl, C2-8alkinyl, cycloalkyl, trifluoromethyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, arylC1-8alkyl, aryl, aryloxy, arylamino, C1-8alkylcarbonyl, arylcarbonyl, arylcarboxyl, arylcarboxyamide, halogen, CN, NRRxe2x80x2, C1-8alkylamino, heterocycle wherein the groups alkyl, alkenyl, alkinyl, cycloalkyl, aryl, heterocycle, can be substituted;
n is an integer comprised between 1 and 4;
and their pharmaceutically acceptable salts or esters,
starting from commercially available, or easily preparable compounds, and involving only three steps.
Compounds of general formula (I) as above defined are known 5xcex1-reductases inhibitors useful for the treatment of the pathologies mediated by the enzyme (for example acne, baldness, prostatic cancer and hypertrophy in men and hirsutism in women) (see International Application No PCT/EP97/00552). They are also active as plant growth regulators.
As it is described in the above said patent application, up to now the compounds of formula (I) are produced by a process involving various steps starting from a compound of formula II 
According to the process the amide-group of compound II is protected as N-Boc derivative, the obtained compound is reduced, reacted with a silyloxydiene produced xe2x80x9cin situxe2x80x9d and hydrolized to obtain a compound of formula III 
Finally the introduction of the double bond in position b is performed by reaction with dichlorodicyanoquinone with the corresponding silylenolethers or by oxidation with mercuric acetate.
As it can be seen the above described process involves many steps which i.a. have a negative effect on the final yields of the desired compounds.
In view of the importance of these compounds as 5xcex1-reductase inhibitors, it is evident the interest in making available new processes in order to prepare the desired compounds in a more efficient way.
The present invention allows to overcome the above said problems by a synthesis process that involves only three steps and moreover uses, as starting compounds, compounds which can be easily synthesized or are commercially available.
According to the present invention in the compounds of formula (I) group C1-8alkyl, C2-8alkenyl and C2-8alkinyl represent linear or branched alkyl radicals as for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, ethylene, propene, butene, isobutene, acetylene, propine, butine ecc.
The term cycloalkyl represents: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, canphane, adamantane.
The term aryl represents: phenyl and naphtyl.
The term heterocycle represents in particular: saturated or aromatic heterocycles containing one or more N atoms, more particularly: pyridine, imidazole, pyrrole, indole, triazoles, pyrrolidine, pyperidine.
Halogen means: fluorine, chlorine, bromine, iodine.
The substituents of the above said group W are preferably: halogen, OR, phenyl, NRRxe2x80x2, CN, COOR, CONRRxe2x80x2, C1-8alkyl (wherein R and Rxe2x80x2 are as above defined).
In particular, the process according to the present invention allows the preparation of the compounds of formula (I) wherein:
Q=simple bond, CO, CONR, NR (wherein R is as above defined) W=H, F, Cl, Br, Me, t-butyl, C1-8alkoxy, 2,5-dimethylhexyl, trifluoromethyl, 2,5-(ditrifuoromethyl)phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, phenyl, phenyl-C1-8alkyl, C1-8alkylcarbonyl, phenylcarbonyl.
n=1 or 2
R1, R2, R3, R4, R5=H, Me, CN, phenyl, COOR, CONRRxe2x80x2 (wherein R and Rxe2x80x2 are as above defined).
Among the pharmaceutically acceptable esters and salts according to the present invention the following can be mentioned: hydrochloride, sulphate, citrate, formiate, phosphate.
Specific compounds prepared according to the process of the invention are:
2,3,5,6-tetrahydro-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-8-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,8-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,4-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-6-methyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-6-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-6,8-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,4,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-5-methyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5,8-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5,8-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1,5-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1,4,5-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-5,6-dimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-5,6,8-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-4,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-1 ,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
8-chloro-2,3,5,6-tetrahydro-1,5,6-trimethyl-(1H)-benzo[c]quinolizin-3-one;
2,3,5,6-tetrahydro-4,5,6,8-tetramethyl-(1H)-benzo[c]quinolizin-3-one.
According to the invention the above defined compounds of formula (I) can be prepared starting from compounds of general formula 2 and 3: 
wherein R1, R2, R3, R4, R5, W, Q and n are as above defined.
The compounds 2 and 3 are commercially available or can be prepared according to known techniques.
As it can be seen from the Scheme 1 the preparation of the compounds I according to the invention involves the N-alkylation of the thioamide 3 with the vinyl ketone 2 to give the N-alkylated thioamide 4 in the presence of a strong, but not nucleophilic, base. Preferably the reaction is performed in an organic solvent (for example THF) at a temperature comprised between 0xc2x0 C.-30xc2x0 C. for a time comprised between two and four hours. More preferably the vinyl ketone is added to the thioamide intermittently.
The characteristics of the base are crucial for the effectiveness of the reaction: indeed strong nucleophilic bases cause the polymerization of the vinylketone, whereas with mild bases the reaction does not occur. Preferred bases having the above said characteristics are: K2CO3/18-crown-6 or diazabicycloundecene (DBU). The N-alkylated thioamide 4 is then methylated at sulfur atom, to give the salt 5, which is not usually isolated, but left to react with a base to give the final compound 1. Also for this step the reaction conditions (temperature and time) and the type of base are important.
The best results were obtained using dimethyl sulfate as methylating agent, a strong but not nucleophilic base (for example DBU) and performing the reaction at refluxing temperature in an organic solvent (for example toluene) for a time comprised between half-and one hour.
The synthesis of two compounds of formula (I) is reported in the following examples in order to better illustrate the invention.